1. Field of the Invention
This invention relates to a method and composition for controlling scar formation and more particularly to the use of Paclitaxel and/or Colchicine and/or penicillamine for the inhibition of wound contraction and scar overgrowth while enhancing epithelialization.
2. Related Art
Wound contraction is the primary process by which wounds decrease their surface area over time. In World War I, contaminated wounds were allowed to heal secondarily by contraction resulting in reduced wound infection and sepsis. Wound contraction, however, frequently results in contractures and functional impairment, the extent of which depends upon the size and location of the wound. Previous studies using systemic or local drug therapy to inhibit contraction have produced inconsistent results, and there is not a single drug that is effective in controlling wound contraction clinically. Contractile fibroblasts and nascent collagen in granulation tissue have been implicated as having an important role in initiating and maintaining wound contraction. Ehrlich, et al. EVIDENCE FOR THE INVOLVEMENT OF MICROTUBULES IN WOUND CONTRACTION, Am. J. Surg., Vol 133, pages 706-709, 1977.
Colchicine has been administered orally to treat scleroderma and coronary restenosis, albeit with limited efficacy, primarily because of systemic toxicity associated with prolonged use of this drug. Colchicine has been shown to stimulate collagenase activity. Colchicine also inhibits many microtubule dependent processes including but not limited to fibroblast cell contraction and motility. Ehrlich, et al., applied Colchicine (10.sup.-5 M) topically to granulating wounds in rabbits and demonstrated that it inhibited contraction but resulted in local tissue death and a tendency towards infection. More recently, however, Rennard et al., COLCHICINE SUPPRESSES THE RELEASE OF FIBROBLAST GROWTH FACTORS FROM ALVEOLAR MACROPHAGES IN VITRO, Am. Rev. Respir. Dis. Vol 137(1), pages 181-185, 1988, demonstrated that Colchicine (40 ng/ml and 100 ng/ml) significantly inhibits secretion of two mediators of fibroblast proliferation (fibronectin and a macro-phage-derived growth factor) in vitro with detectable inhibition in the range of 1-10 ng/ml. The effect of Colchicine was not due to nonspecific toxicity since macrophages treated with Colchicine were capable of de novo protein synthesis and secretion of several protein products, despite the fact that fibronectin and growth factor release were suppressed. Notable also is the recent work of Damji et al., PHARMACOLOGIC MODULATION OF HUMAN SUBCONJUNCTIVAL FIBROBLAST BEHAVIOR IN VITRO, Ophthalmic. Surg., Vol. 21, No. 1, pages 31-43, 1990, who demonstrated that Colchicine inhibited cell migration at 0.004, .mu.g/ml without cytotoxicity. These two studies prompted an evaluation of Colchicine, in vivo, at concentrations lower than 10.sup.-5 M, administering the drug by local injection. It was postulated that by injecting Colchicine at low concentrations directly into the wound, the toxicity associated with applying the drug topically could be eliminated.
Penicillamine has been shown to demonstrate efficacy in the treatment of rheumatoid arthritis and Wilson's disease. It blocks cross-linking of newly formed tropocollagen and degrades a certain fraction of the more recently synthesized collagen. It has also been shown to have potent antiinflammatory properties. Rennekampiff et al., REDUCTION OF CAPSULAR FORMATION AROUND SILICON BREAST IMPLANTS BY D-D-PENICILLAMINE IN RATS, Scand. J. Plast. Reconstr. Surg. Hand. Sur. Vol. 26, No. 3, pages 253-255, 1992 demonstrated reduced capsular adhesion formation in rats around silicon implants using penicillamine in subcutaneously implanted osmotic minipumps. Penicillamine has been associated with the formation of less severe esophageal stricture in rabbits.
In the paper by Joseph. et al., INHIBITION OF WOUND CONTRACTION WITH COLCHICINE AND D-PENICILLAMINE, published Feb. 15, 1996 in the Journal of Surgical Research, Vol. 61, No. 1, pages 197-200, the effects of locally injected combined Colchicine and D-penicillamine on wound contraction were investigated in a murine model. The data suggested that very low concentrations of Colchicine and D-penicillamine only when combined and injected locally is potentially useful in controlling surface scar formation. The drugs used alone did not significantly alter scarring.
Another drug, Paclitaxel is a well-known chemotherapeutic drug for the treatment of various metastatic cancers. It has been approved by the Food and Drug Administration (FDA) for the treatment of ovarian and breast cancers and is currently in clinical trial for the treatment of lung and colon cancers.
The compound is a natural product primarily extracted from the bark of the PuYew tree, Taxus brevifolia, and also found in T.baccata, T. walichiana and T. wunnanensis and other biomass extracts from plant material. Aquataxul is also available from cultured plant cells and fungi.
U.S. Pat. No. 4,485,088 to Chvapil discloses a method of treating fibrotic lesions related to abnormal collagen polymerization by local administration of lathyrogen substance and D-penicillamine into the site of the injury. The lathyrogenic drugs are administered by local injection or onto the skin and percutaneously transported into the lesion.
Wounds heal by contraction and scar formation. Wound contraction is the process by which wounds decrease their surface area over time. Wound contraction however, frequently results in functional impairment because of the involvement of the adjacent tissues, the extent of which depends on the size and location of the wounds. The mechanisms of these processes are not completely understood; consequently, surgeons are unable to alter the outcome in most patients. In patients with large wounds, wounds on the face and burns, permanent disfigurement and lifelong functional limitations often result.
What is needed, and is not heretofore been developed is an effective combination of drugs which synergistically act or coact to control scar formation through the inhibition of wound contraction.